The invention involves the alleviation of depression, anxiety, and other psychological or mental disorders by administering certain bioactive metabolites of the known anti-depressant compound gepirone. In a preferred embodiment, the compound is 4,4,-dimethyl-3-hydroxy-1-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2,6-piperidinedione (3-OH gepirone), however other gepirone metabolites and combinations thereof are possible and contemplated. Surprisingly, these bioactive metabolites of gepirone show improved bioavailability characteristics and improved potential for immediate action and long-term treatment regimens when compared to gepirone and other therapeutic azapirones. Accordingly, the invention provides new and improved methods for treating a variety of psychological disorders and conditions.
The use, preparation, and characterization of therapeutic azapirone compounds has been disclosed in numerous documents (see Cadieux, Amer. Family Physician 1996 53: 2349-2353; Temple, U.S. Pat. No. 4,423,049; Gawin, U.S. Pat. No. 5,185,329; Madding, U.S. Pat. No. 5,521,313). This class of compounds attributes its activity to partial agonism of the 5-HT1A receptor.
Clinical studies of known 5-HT1A agonists and partial agonists, for example buspirone, ipsapirone, and gepirone, have shown that these compounds are useful in the treatment of anxiety disorders, such as generalized anxiety disorder (GAD), panic disorder, and obsessive compulsive disorder (Glitz, D. A., Pohl, R., Drugs 1991, 41:11; Cadieux, Amer. Family Physician 1996 53: 2349-2353). Clinical and preclinical evidence supports 5-HT1A partial agonists for use in treating depression as well as impulse control disorders and alcohol abuse (van Hest, Psychopharm., 107: 474 (1992); Schipper et al, Human Psychopharm., 6: S53 (1991); Cervo et al, Eur. J. Pharm., 158: 53 (1988); Glitz, D. A., Pohl, R., Drugs, 41: 11(199 1)). Studies show that 5-HT1A agonists and partial agonists inhibit isolation-induced aggression in male mammals, indicating that they can be used to treat aggression (Sanchez et al, Psychopharmacology, 1993, 110:53-59). Other studies indicate that 5-HT1A receptors are important in the serotonergic modulation of haloperidol-induced catalepsy (Hicks, Life Science 1990, 47:1609) suggesting that 5-HT1A agonists can be used to treat the deleterious side effects of conventional antipsychotic agents, such as haloperidol. Recent reports show that this is the case for side effects like tardive dyskinesias.
One of the more important azapirones is gepirone, which has the following structure. 
Gepirone has been used to effectively treat anxiety disorders and depression (Casacalenda, Canadian J. of Psychiatry, 43:722-730 (1998)). However, it has several drawbacks from the standpoint of an ideal therapeutic anxiolytic or anti-depressant. It has low bioavailability characteristics when delivered orally, on the order of 14-18%. In addition, the half-life of gepirone is very short. As a result, an extended release formulation of gepirone is preferred so that sustained therapeutic levels can be delivered during a standard regimen without increasing dosage levels. Furthermore, in a small percentage of cases, gepirone has been associated with side effects such as nausea and vomiting. Accordingly, 5-HT1A agonists with improved properties and characteristics are still in need.
Several proposed gepirone-derived compounds were discussed in von Malke, et al., Psychopharmacology, 140: 293-299 (1998). No biological activity for these compounds has been disclosed or suggested. The metabolism of buspirone, perhaps the best known member of the azapirones, was elucidated by Jajoo, et al, Xenobiotica, 20:779-786 (1990). In the metabolic cascade derived from buspirone, one of the seven buspirone metabolites (referred to as 6xe2x80x2-OH-Bu) is the buspirone analog of 3-OH gepirone. No significant biological activity has been disclosed for 6xe2x80x2-OH-Bu.